Beta-ketoacyl-acyl carrier protein synthase III (mtFabH)

Beta-ketoacyl-acyl carrier protein synthase III (mtFabH) is a key regulatory enzyme in the Fatty Acid Synthase II (FAS-II) system of Mycobacterium tuberculosis (UniProt P9WNG3). It catalyzes the initial condensation of acetyl-CoA with malonyl-acyl carrier protein (ACP) to produce acetoacetyl-ACP, serving as the essential link between the FAS-I and FAS-II pathways (Scarsdale et al., 2001, J. Biol. Chem.). This reaction provides the necessary primers for the synthesis of long-chain fatty acids, which are precursors to mycolic acids. Mycolic acids are vital structural components of the mycobacterial cell wall, providing a protective barrier against antibiotics and host immune responses (Brown et al., 2005, Microbiology). Because mtFabH is essential for the viability of M. tuberculosis and lacks a structural homolog in humans, it is a highly attractive target for the development of novel antitubercular agents (PubMed: 21859123). Inhibitors such as the natural product thiolactomycin and various synthetic small molecules aim to disrupt cell wall integrity, offering a mechanism of action distinct from current frontline tuberculosis therapies (NIH/PubChem).

Other names

3-oxoacyl-[acyl-carrier-protein] synthase 3KAS IIIFabHBeta-ketoacyl-ACP synthase IIIBeta-ketoacyl-acyl carrier protein synthase 3

Inhibition of the condensation reaction between acetyl-CoA and malonyl-ACP, which prevents the initiation of the FAS-II fatty acid elongation cycle and subsequent mycolic acid synthesis.